Follow up Questions on Space

Transcription

1 Follow up Questions on Space Radiation Risks Presented to IOM Committee on Ethics Principles and Guidelines for Health Standards for Long Duration and Exploration Spaceflights FrancisA A. Cucinotta, PhD NASA JSC July 18,

2 Follow up Radiation Questions 1) It would be helpful if you could explain the 3% limit a bit more some of the committee have questions about what occupational exposure limits are being used (see below). NCRP 132, refers to excess lifetime risk of cancer mortality (p. 143) compared to the lifetime risks associated with the occupational exposure limits recommended for workers on the ground 2) Cancer effects: How does the rate of cancer incidence compare to the rate of cancer death for a given level of exposure, and to what extent would post mission early detection be an effective risk ikmitigation ii i strategy? 3) Non cancer effects: Can you provide more information about the "short term limits" as defined in NASA Standard 3001 Vol 1, table 4 in Appendix F, specifically those addressing "degenerative" impacts (CNS, cardiovascular, immune system, and skin)? How does the degree of uncertainty inthese effects compare withthedegreethe of uncertainty in cancer REID?

3 1) Radiation Limits Prior to 1989, NASA s career limits were based on recommendations to NASA in a 1970 NAS report. NAS had recommended dose limits be based on estimated doubling dose for fatal cancer risk for 35 year old males. In 1989, the NCRP published their report No. 89 which recommended age at exposure and gender based dose limits using a 3% fatal cancer ce risk as basis s for dose limits (<1 in 33 probability of occupational death)

4 Rationale from NCRP Report No. 98 (1989) The NCRP Report No. 98 made observations on several types of comparative risks in formulating recommendations for NASA. Comparisons included: to ground based radiation worker average doses and dose limits, to fatalities in safe, less safe and unsafe industries, to other risks astronauts incur due to space flight The NCRP noted that ground based Rad workers average doses were similar to risks in safe industries, while their Dose Limits it were similar il to risks ik in less safe f industries, i The NCRP noted that since Astronauts face other risks similar to unsafe industries it would not be appropriate for NASA s radiation limitsto to be similarto risks in unsafe nsafe industries. The NCRP therefore recommended Risk limit of 3% (<1 in 33 chance of fatality) similar to less safe industries risks in 1980 s s, and coinciding withground ground based Rad worker limits.

5 NCRP Report No. 132 (2000) The NCRP Report No. 132 noted that the risks in the less safe industries were reduced since the 1980 s, however recommended NASA maintain a 3% Limit similar to risk of ground based Rad workers if they reached lifetime dose limit. Similar discussion was considered in NCRP, Acceptability ofriskfrom from Radiation Application to Human Space Flight. Bethesda, MD, NCRP Symposium Proceedings No. 3, 1997.

6 Risk in Less Safe Industries have decreased to <1% Annual Fatality Rates from Accidents in Different Occupations noted by NCRP Report 98 (1989) a, NCRP Report 132 (2000) b, and recent values from National Safety Council c. Percent probabilities for occupational fatality for careers of 45 years are listed in parenthesis. Occupation Annual Fatal Accident Rate per 100,000 workers (%Lifetime Fatality for 45 y career) 1987 a 1998 b 2009 c Safe Manufacturing 6 (0.27%) 3 (0.14) 2 (0.1) Trade 5 (0.23) 2 (0.1) 43(0 4.3 (0.2) Services 5 (0.23) 1.5 (<0.1) 2 (0.1) Government 8 (0.36) 2 (0.1) 1.8 (<0.1) Less Safe Agriculture 49 (2.2) 22 (1.0) 25.4 (1.1) Mining 38 (1.7) 24 (1.1) 12.8 (0.58) Construction 35 (1.6) 14 (0.63) 93(0 9.3 (0.42) Transportation 28 (1.3) 12 (0.54) 11 (0.5) ALL 10 (0.45) 4 (0.18) 2.8 (0.13)

7 2) Cancer Risks Role of Early Detection Early Detection could improve survival rates NCI Report 5 year survival rates for All Lung cancer in M/F of 14/19% and for Stage I Lung cancers for M/F of 54/65% Participation in more extensive Early detection would be up to the individual. dua There is no evidence of improved survival for astronaut cancers that have occurred to date. Ratio of CancerIncidence to Mortality for Astronauts is similar to U.S. Average. For e.g., excluding Prostate and Skin cancers: US Average Survival 59%, Astronaut Survival 44% [25,66]% The likelihoodofimproved of improved cancer survival through early detection also depends on the type of tumors that occur. NASA funded animal studies show GCR produce more aggressive tumors compared to control, gamma rays or SPE induced tumors

8 Qualitative Differences in Cancer Risks from GCR PELs and NSCR 2012 only accounts Incidence of Malignant Liver Tumors in Mice for quantitative differences using 30 Si 350Mev Quality Factors (QFs). 25 1GeV Fe 20 Gamma SPE acute Issues emerging from research studies of GCR Solidcancer risks. Earlier appearance and aggressive tumors not seen with controls, gamma rays or proton tumors Non linear response at low dose due to Non Targeted Effects confounds conventional paradigms and RBE estimates SPE (proton) tumors are similar to background tumors These issues are called out in NCRP reports and NRC reviews. Tum mor Incidence (%) Dose (Gy) Fe 600MeV A. Tumor Latency vs Time After exposure rays 600 Mev/amu Fe p< B. Tumor Types 600 Mev/amu Fe rays 8

9 GCR Heavy ions produce more aggressive tumors compared to controls or X ray tumors Tumor pathology in Apc 1638N/+ Effect of Radiation Quality on Tumor Grade in Colon Tubulovillous adenomas Invasive carcinoma -rays protons 56 Fe Trani D. et al., In preparation 14 UTMB NSCOR- PI Robert Ullrich Shows much higher occurrence of metastatic Liver (HCC) tumors from GCR Fe or Si nuclei compared to gamma-rays or protons Georgetown NSCOR- PI Al Fornace Shows much higher occurrence of invasive carcinomas tumors from GCR Fe nuclei compared to gamma-rays or protons 9

10 3) Non Cancer Effects Short term limits" for Non Cancer Risks are defined in NASA Standard 3001 Vol 1, table 4 in Appendix F are intended to protect against Early radiation effects and late Degenerative. Effects: Early: Blood System, Skin Late Degenerative Risks: Cataracts, Circulatory Diseases, CNS Risks Other effects may occur but most likely at higher doses so specific dose limits are not considered (e.g., prodromal risks are prevented tdby BFO limit). it) Question: How does the degree of uncertainty in these effects compare with the degree of uncertainty in cancer REID?

11 Non Cancer Effects RiskLimits NASA limits acceptable levels of risks of astronauts to a 3% Risk of Exposure Induced Death (REID) from cancer. The NCRP recommends that limits for non cancer morbidity risks be based on avoiding any clinically significant effect. Basisfor past NASA non cancer dose limits Many Non cancer effects have dose thresholds and importance of limits is overwhelming: BFO, and Skin Damage Uncertainties exist in determining the dose thresholds, RBE, and dose rate modifiers 11

12 Non cancer risk limits continued In some cases Non cancer risks are not well defined. In flight Central Nervous System (CNS) risks Research in cells and mouse/rate models are not conclusive regarding clinical i l significance ifi of space radiation on the CNS in humans Need appropriate animal model to assess clinical significance Clinical significance of cataracts associated with past space radiation exposures reported in 3 NASA publications needs further study Uncertainty estimates await further radiobiology research on these risks.

13 Non cancer risk limits continued In other cases the detriments are well known if the risk occurred. Circulatory disease and Alzheimer s diseases lead to fatality Depending on research findings, NASA would need to include these risks in the %REID, and re consider Acceptable risk levels for other late mortality risks and the associated morbidity risks Placeholder dose limits were assigned in NASA PEL s in 2005 assuming dose threshold occur, however Circulatory and Alzheimer s disease risk may occur without threshold for GCR and then would need to be included din an aggregate risk iklimit i with ihcancer Uncertainties can be estimated for Circulatory Disease risks, however immature compared to cancer uncertainty estimates. Uncertainties for late CNS risks await further research findings.

14 Other material 14

15 Non Cancer PELs (NASA Standard 3000) Table-IIa. Dose limits for Short-term or Career Non-Cancer Effects (in mgy-eq. or mgy). Note RBE s for specific risks are distinct as described below. Organ 30 day limit 1 Year Limit Career Lens a 1000 mgy-eq 2000 mgy-eq 4000 mgy-eq Skin BFO b Not applicable Heart c CNS d e CNS e (Z 10) mgy 250 mgy a Lens limits are intended to prevent early (<5 yr) severe cataracts (e.g. from a solar particle event). An additional cataract risk exists at lower doses from cosmic rays for sub-clinical cataracts, which may progress to severe types after long latency (>5 yr) and are not preventable by existing mitigation measures, however are deemed an acceptable risk to the program. b BFO Dose calculations exclude doses from a large SPE and averaged over active marrow sites as described by Christy (1981) c Heart doses calculated as average over heart muscle and adjacent arteries. d CNS limits should be calculated at the hippocampus. 15

16 Meta Analysis for Circulatory disease from Radiation (Little et al. Env. Health Persp (2012)) Most Humans Studies show excess risk even at doses < 1 Sv CVA = Cardiovascular Disease IHD = Ischemic Heart Disease

17 Risk for Exploration Missions: Cancer and Circulatory Disease PC = Probability of Causation at 10 years Post-exposure. If cancer or circulatory disease is discovered d in crew member, PC is probability space radiation was cause

18 Risk for Exploration Missions: Cancer and Circulatory Disease ISS = International Space Station; lower risk because GCR partially shielded by Earth Shadow and Magnetic Field Mars Opposition: 60-d on mars surface with variable transit time (480 to 720-d) Mars Conjunction: 540-d on martian surface with 400-d transit time

19 CNS Risks from Galactic Cosmic Rays (GCR) Retinal flashes observed by astronauts suggests single heavy nuclei can disrupt brain function CNS damage by x rays isnot observed except at high doses In flight cognitive and short term memory changes and late effects similar to Alzheimer s disease are a concern for GCR. NASA research in cells/mouse/rat models has increased concern for CNS Risks Over 120 CNS journal publications supported by NASA since 2000 Studies show neuronal degeneration, oxidative stress, apoptosis, inflammation, and changes in dopamine function Cognitive tests in rats/mice show detriments at doses as low as 10 mgy (1 rad) at early times after exposure Low doses of GCR alter the creation of new neurons in mice and rats, disrupting new memory and cognition Large hurdle remains to establish significance in humans Early CNS changes on Motor function in the Neostratium (J. Josephs et al. Rad Res, 1992) Low Dose 56 Fe particle irradiation leads to Early Alzheimer s Disease Biomarkers of AD are shown in mice at different dose levels Cherry JD, Liu B, Frost JL, Lemere CA, et al. (2012) Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer s Disease. PLoS ONE 7(12): e doi: /journal.pone

20 CNS Radiation Injury NASA studies have seen effects in hippocampus, neostratium and pre frontal cortex 200 Apoptosis and overt loss of cellular 150 constituents is minimal (most brain 100 cells are not actively dividing) idi 50 0 Late effects predominant and may arise from: Loss of progenitor populations (neurons & glia) Persistent inflammation Persistent oxidative changes Interdependency of neural elements for normal function (e.g. supporting glia and vasculature) must be recognized Cells No. Dcx-positive Gy 1 Gy 2 Gy 3 Gy Reduction in number of neurons (neurodegeneration) for increasing Iron doses in mouse hippocampus (J. Fike, UCSF) Control Iron irradiated Oxidative Stress (Lipid peroxidation:4-hydroxynonenal) is Increased in Mouse Hippocampus 9 Months After 2 Gy of 56 Fe Irradiation

21 Acute CNS Effects from GCR on Memory/Cognition (PI J. Raber) J. Raber/OSU shows loss of memory/cognition at low doses of HZE particle irradiation at early time points (as early as 2 weeks after radiation) in C57BL6/J male and female mice. Measures of Oxidative stress are not impacted in same animals, It is possible that oxidative damage might contribute to radiation induced cognitive changes. Therefore, hippocampal and cortical levels of 3 nitrotyrosine (3NT) and lipid peroxidation, measures of oxidative damage were assessed. There were no effects of irradiation on these measures of oxidative damage...the effects of the antioxidant alphalipoic acid (ALA) on cognition following sham irradiation and irradiation were also assessed. ALA did not prevent radiation induced impairments in novel object recognition and impaired spatial memory retention of shamirradiated and irradiated mice in the probe trial after the first day of hidden platform training in the water maze. Thus, the novel object recognition test is particularly sensitive to detect early cognitive effects of 56Fe irradiation through a mechanism unlikely involving ROS or oxidative damage 21

22 Space Radiation Safety Requirements Congress has chartered the National Council on Radiation Protection and Measurements (NCRP) to guide Federal agencies onradiation limits and procedures. Safety Principles of Risk Justification, Risk Limitation and ALARA (as low as reasonably achievable) Crew safety: limit of 3% fatal cancer risk based on 1989 comparison of risks in less safe industries NASA limits the 3% lifetime fatality risk at a 95% confidence level to protect against uncertainties in risk projections Placeholder ld requirements in PEL limit it Central Nervous System (CNS) and circulatory disease risks from space radiation Limits set Mission andvehicle Requirements. shielding, dosimetry, countermeasures, & crew 22

23 NASA Permissible Exposure Limits (PELs) NASA Standard is 95% Confidence level for Risk of Exposure Induced Death (REID) less than 3%. Less than 1 in 33 chance of early death Best estimate t is 20 years average life loss for space radiation attributable cancer Risk are reported as CR[A, B]: Where: CR = central estimate of risk A= Lower 95% Confidence Interval B = Upper 95% Confidence interval (NASA Standard) The NASA Space Cancer Risk (NSCR) model was reviewed by the National Research Council in Basis for estimating crew risks for ISS missions and trade studies of future Exploration class missions Several newfeatures ofnscrmodelimprove NASA s risk assessments. Risks for Lifetime Never smokers, lowers space radiation risk compared to U.S. Ave population of about 20% New Quality factors and improved Uncertainty estimates Uncertainty Components 23